Mytho/Phaf1 is required to prevent DNA damage and tissue degeneration in Danio rerio.

Abstract

mytho (Macroautophagy and YouTH Optimizer) is a novel FoxO-dependent gene that has been recently identified to control health- and life-span in Caenorhabditis elegans via autophagy regulation. However, the role of this gene in tissues development and function in vertebrates has not yet been established. To address these issues, we generated a zebrafish mytho KO model and observed that mutants exhibited a higher mortality rate than wild-type (WT) siblings during the first month of life and a lower resistance to oxidative stress. mytho silencing resulted in a decrease in larval locomotor activity and muscle birefringence and caused alteration of adult muscle structure. Autophagy impairment was confirmed in tissues with the highest mytho expression such as brain, muscle and testis. Finally, mutants showed tissue degeneration in pancreas, retina and muscle, morphological alterations in gonads of both sexes and a reduction of reproductive capabilities of males. Importantly, males presented a higher incidence of seminomas, a testicular cancer. The increased susceptibility to cancer is associated with an enhanced DNA fragmentation in sperm cells. In conclusion, this study highlights the key role of Mytho in maintaining proper tissue function and DNA integrity.